Project 2: TAU Abstract: The neuropathologic definition of Alzheimer's disease (AD) relies on the presence of two well-characterized protein aggregates in the brain, amyloid-beta (A) plaques and hyperphosphorylated tau in the form of neurofibrillary tangles. The widespread use of A positron emission tomography (PET) imaging technology has helped identify the prevalence of significant A deposition in vivo in the elderly population, in which elevated levels of A are found in about 30% of cognitively normal elderly (NC) subjects at a mean age of about 75 years old, 60% of mild cognitive impairment (MCI) subjects, and 90% of clinically diagnosed AD subjects. Efforts to develop tau-selective PET imaging agents have been successful recently with the application of several new tau PET radioligands, including the radioligand [18F]T807 (T807). We propose to characterize the behavior of T807, in concert with other biomarkers of neurodegeneration, in NC, MCI, and AD subjects. In cross-sectional studies, we will investigate regional differences in brain tau load in the different subject groups and compare the in vivo topology of abnormal tau deposition with the pattern predicted by postmortem Braak staging. We will leverage existing data on [18F]2-fluoro-2-deoxy-D-glucose (FDG) hypometabolism, hippocampal volume (HV) loss, [11C]Pittsburgh Compound-B (PiB) measures of A load, and cognitive performance measures in subjects recruited from NC, MCI and AD cohorts at the University of Pittsburgh in whom these biomarker measures have been obtained with separate funding to correlate with the T807 PET results. Following cross-sectional evaluation of tau load in the different groups, we will rescan all subjects using T807 at 30 months to evaluate longitudinal changes in T807 signal and compare tau changes with changes in the other biomarker measures in the same subjects. The combination of in vivo tau and A imaging has the potential to provide a more complete view of the pathological progression of AD from prodromal to end-stage phases. Three NC groups will be evaluated in the proposed studies and compared to amyloid-positive MCI and AD groups. These NC groups include: amyloid-negative NC with no abnormal FDG and HV markers (Stage-0 NC); amyloid-positive NC with or without abnormal FDG and/or HV markers (Stage-1 and Stage-2 NC); and amyloid-negative NC with abnormal FDG and/or HV markers, characterized as suspected non-amyloid pathophysiology (SNAP) . Early studies indicate that some SNAP subjects may be on an AD pathway of cognitive decline and some may be on non-AD pathways. It is not clear whether neocortical tauopathy precedes A abnormalities in SNAP subjects or whether the order of tau vs. A dysregulation will distinguish which pathway SNAP subjects take. In vivo topographic changes in tau deposition relative to changes in A deposition will be determined using T807 PET imaging in concert with PiB PET imaging. It is anticipated that the use of both T807 and PiB in these studies will help clarify the temporal sequences of tau and A changes in mesial temporal cortex and neocortical brain regions in normal aging and in AD pathways.